INFECTION BY HPV IN THE ORAL CAVITY-A LITERATURE REVIEW INFECÇÃO POR HPV NA CAVIDADE ORAL-REVISÃO DA LITERATURA

Human papillomavirus (HPV) is a microorganism that has the potential to infect the skin and mucous membranes, causing local tissue injury or remaining asymptomatic. When one’s immune system is not capable of fighting an invasion of the virus, it remains latent inside the nucleus of infected cells. One of the clinical manifestations is the presence of benign epithelial lesions in the oral cavity, which include squamous cell papilloma, common skin warts, focal epithelial hyperplasia and papillary hyperplasia. Human papillomaviruses have an etiological role in cancers of the pharynx and the oral cavity, with 25-50% of cases being attributed to HPV infections. A literature review was carried out in big contemporary databases and included papers from any year of publishing, going back as far as reviewing the history of its viral taxonomic classification all the way to current clinical approaches and therapies to patients with this infection, as well as immunization strategies with vaccines. It has been observed that the development of oropharyngeal cancer in a younger and non-smoking population could be attributable to HPV as an independent causal factor and has been a subject of increasing interest for the research community. HPV vaccination is expected to impact oral HPV incidence rates, leastwise for the genotypes included in the vaccine.


INTRODUCTION
The human papillomavirus (HPV) is a small (55nm), non-enveloped, icosahedral shaped virus, with a natural tropism or predilection to infect epithelial cells (HA; CALIFANO, 2004). It can cause tissue lesions or remain in a dormant non-replicative state (BERNARD et al., 2010). More than 200 types of HPV have already been identified, all capable of infecting skin cells or cells of mucous membranes. They are divided into high and low risk subtypes (HÜBBERS; AKGÜL, 2015).
The HPV infection is basically transmitted through any sexual contact (FERNANDES et al., 2013) both men and women are susceptible to the infection, and can be asymptomatic carriers, transmitters and affected by the infection, all at once in some cases (TRISTÃO et al., 2012). Among all of the risk factors for HPV infection, the following stand out: having a high number of sexual partners, tobacco use, alcohol consumption, early age of sexual activity initiation and use of oral hormonal medications (FERNANDES et al., 2013;GASPAR et al., 2015;SANTOS, et al., 2016).
HPV has the molecular mechanisms necessary to infect the cells of the basal layer of the epithelium, when there is solution of continuity of the outermost layer of the skin. Although most often the virus is eliminated by the immune system, not leading to clinical disease. When the immune response is insufficient, the virus enters a quiescent state, and remains dormant inside the nuclei of the infected cells (HORMIA et al., 2005;HENNESSEY;WESTRA;CALIFANO, 2009).
One of the clinical manifestations is the presence of benign epithelial lesions in the oral cavity, those which include squamous cell papilloma, condyloma acuminatum, common warts, focal epithelial hyperplasia and papillary hyperplasia (ABBEY et al., 1980). Oral squamous papiloma is the most frequently presented lesion and occurs evenly among genders, predominantly in the tongue and soft palate (FERRARO et al., 2011).
In the oral cavity, HPV subtypes are classified according to their respective oncogenic risk, subtypes 6 and 11 are considered low risk variants and are associated with benign oral lesions, such as warts, condyloma acuminatum, papilloma, and focal epithelial hyperplasia. High risk subtypes such as HPV 16 and 18, on the other hand, are frequently associated with squamous cell carcinoma and precancerous lesions with a high risk of malignization (D ŚOUZA et al., 2007).
Human papillomaviruses play an etiological role in cancers of the oropharynx, with 25-50% of cases being attributed to HPV infections (DE MARTEL et al., 2017;CHATURVEDI et al., 2013).
In particular, the incidence of cancerous lesions in a younger, non-smoking population has raised the attention of the research community (ZAMMIT et al., 2018).
Currently, the two most frequently used methods to detect the viral genome are the hybrid capture method and polymerase chain reaction (PCR) with generic primers. There is no knowledge reliable method that can determine causality between the presence of the virus and the disease, Disciplinarum Scientia. Série: Ciências da Saúde, Santa Maria, v. 21, n. 3, p. 45-64, 2020. 47 although its presence is highly suggestive (HUBBARD, 2003). Vaccinating against HPV is expected to have an impact on the rates of incidence of oral HPV, lowering the prevalence of HPV genotypes 6, 11, 16 as well as 18. Which are included in the vaccine (BROUWER et al., 2015).
A literature integrative review was carried out in big contemporary databases and included papers from any year of publishing, going back as far as reviewing the history of its viral taxonomic classification all the way to current clinical approaches and therapies to patients with this infection, as well as immunization strategies (old and new) with vaccines. The term oral papilloma was used, articles that searched for HPV in malignant tumors were exclused.
It infects the epithelium of some vertebrates, including humans, where it remains asymptomatic/ quiescent or may evoke symptoms (BERNARD et al., 2010). Complete genomes of the Papillomaviridae family were identified in 1949 (STRAUSS et al., 1949).
In 1963, HPV's viral genome was unveiled. (CRAWFORD, 1963). Its DNA was purified from wart samples. The physical maps of the length of base pairs in generated genomes were compiled (FAVRE et al., 1975). In one of the first conventions on papillomaviruses, Coggin and Zur Hausen, making an attempt to unify nomenclature, established that the Human Papilomaviruses would be attributed a given number, in the order in which their discovery was published. Hence, the first isolate would be their prototype. Also, a new type of HPV could be labeled if any new circular double stranded DNA molecule with less than 50% of base pair similarity to other previously labeled HPV types, was discovered. The similarity should be determined using liquid hybridization methods, under strict conditions. All HPV types had at least six "early" genes (E1 -E7) and two "late" genes (L1, L2), as well as a loci known as regulatory regions (DE VILLERS, 2013).
HPV was also found in reptiles, birds and other mammals. Thence, the heterogeneity of species found to be susceptible to this virus reflects not only the velocity in which the pathogen acquired its genomic mutations, but also a notably antique story of adaptations to specific host cells, and hostmediated control of infections (DE VILLERS et al., 2004).
Over 200 HPV types were already identified, they're grouped in 5 genera (Alphapapillomavirus, Betapapillomavirus, Gammapapillomavirus, Mu papillomavirus and Nu papillomavirus) and are also divided in high and low risk HPVs, according to their oncogenic risk. HPVs can also be divided in regard to their tropism for particular tissue types, being divided as mucous or cutaneous (HÜBBERS; AKGÜL, 2015).

GENOTYPE & SUBTYPE CLASSIFICATION
About 30 years ago, the labeling and subdivision of HPV types was initiated, but the absence of a reliable cell culture system to replicate this virus, postponed its taxonomic classification. (DE VILLERS et al., 2004). New techniques have allowed the discovery of new viral types. (DE VILLERS, 2013).
The strict fastidiousness of papillomaviruses to replicate on the terminal differentiation of keratinocytes, initially hampered its proper study and classification. At first, it was impossible to propagate virions in cell culture, and viral yields from natural lesions were low, with few exceptions. The use of DNA-free virus-like particles (VLPs), virions generated in organotypic cultures and pseudovirions containing plasmid markers, which were generated using heterologous expression or cell-free packaging systems, helped partially to overcome this problem (BIENKOWSKA-HABA; SAPP, 2011).
There was an attempt to recognize the official classification for papillomaviruses by the Knowledge of the conserved L1 gene led to the development of primers for its use in taxonomic classification into types and subtypes (MANOS et al., 1989). Papillomavirus genotypes were classified according to the L1 gene, which encompasses a preserved open reading frame (ORF). Similarity of at least 90% of the L1 nucleotide sequence characterizes the viral type (genus) and the discrepancy of 2 to 10% in the sequence code classifies a subtype (species).
Claude Fauquet et al. (2003) had an essential role in the preparation of the proposal (including 96 types of HPV and 22 animal viruses), and influenced the final decision of the ICTV (International Committee on Taxonomy of Viruses), in which the classification of the Papillomaviridae family was accepted as it currently is today (DE VILLERS et al., 2004). De Villers et al. (2004) described the topology of phylogenetic trees, set quantitative thresholds in analyses of nucleotide sequences and biologically distinctive characteristics (host species, target tissues, pathogenicity, genome organization) that ultimately determine the classification of these viruses at the genus level. A nomenclature of these genera based on the Greek alphabet was introduced and quickly became accepted and widely used by the ICTV and the papillomavirus research community.
In 2004, sixteen papillomavirus or individual groups met the genera criterion, and the Greek alphabet from the letters alpha to pi was used to create their nomenclature. Human papillomaviruses were then separated in five genera (Alpha, Beta, Gamma, Mu and Nu-PVs) and the two remaining Disciplinarum Scientia. Série: Ciências da Saúde, Santa Maria, v. 21, n. 3, p. 45-64, 2020. 49 genera (Eta-and Theta-PVs) comprised a single bird papillomavirus (FAUQUET et al., 2005;BERNARD et al., 2010).
The E region is expressed soon after infection, and codes for proteins responsible for promoting and regulating DNA synthesis. It is encompassing genes E1, E2, E4, E5, E6 and E7. The L region codes for proteins in the viral icosahedral capsid, and is formed by genes L1 and L2. In between the Disciplinarum Scientia. Série: Ciências da Saúde, Santa Maria, v. 21, n. 3, p. 45-64, 2020.

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L and E regions, is the long control-region (LCR), that does not code for any proteins, but regulates viral transcription (SOUZA; GONÇALVES, 2009;SUN et al., 2009).
The L1 and L2 proteins are encoded in the late region and are responsible for forming the viral capsid. The capsid is composed of 360 molecules of the L1 protein, which are arranged in 72 capsomeres organized in pentameric structures, and 12 molecules of the L2 protein (BIENKOWSKA-HABA; SAPP, 2011). The L1 protein has multiple functions; one of them is mediating the viral binding to the cell surface, while the L2 protein is responsible for programming the inclusion of the viral genome in the capsid, hence promoting the assembly of the virion (FAY et al., 2004;STAUFFER et al., 1998).
The E region genes encode three oncoproteins, E5, E6 and E7. The E5 protein is responsible

INFECTION CHARACTERISTICS
The entry of HPV into the host cell depends on the binding of heparin sulfate onto the host's basement membrane, this binding trigger conformational changes that affect structural proteins L1 and

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shown a high prevalence, mainly in the Northeast of Brazil (BRUNO et al., 2014). Some studies have suggested an increased risk of infection in HIV patients. (COUTLÉE et al., 1997;PALEFSKY, 2006). Authors are unanimous in stating that subtypes 16 and 18 are the most frequently found in the oral mucosa (FURRER et al., 2006;SYRJÄNEN, 2003). A meta-analysis study showed that the subtype mostly associated with squamous cell carcinoma is HPV-16, followed by 18, 45, 31 and 33. In adenocarcinomas, the most common is HPV-18, followed by 16 and 45 (CLIFFORD et al., 2003). Ostwald et al. (2003)

CLINICAL MANIFESTATIONS
Benign epithelial lesions in the oral cavity include squamous cell papilloma, condyloma acuminatum, common skin wart, focal epithelial hyperplasia and papillary hyperplasia. Comprehensive data on the prevalence of these benign lesions of the oral mucosa are incomplete, without systematic population-based studies. Based on an old survey of 400,000 American children, oral papilloma's were the most common (7.5%) oral epithelial lesions. Their prevalence was lower in adults, ranging from 0.2% to 0.4%, most often located on the palate, tongue, lips or gums. (ABBEY et al., 1980).

All of these benign epithelial lesions have been attributed to human papillomaviruses (HPV).
Recently it was demonstrated that both β and γ HPVs can also be detected in the oral mucosa and / or saliva in asymptomatic infected patients (BOTTALICO et al., 2011), as well as in head and neck carcinomas (SABOL et al., 2016).
The general prevalence of HPV varies according to the anatomical topography, such as the oral cavity (24.2%), the oropharynx (45.8%) and the larynx (22.1%) (D'SOUZA et al., 2007). In a study that investigated lesions located strictly in the oral cavity, the etiological fraction of HPV infections was low (5.9%) (ANANTHARAMAN et al., 2017). Oral HPV infection is not only associated with but may also precede the onset of oropharyngeal cancer (SHIN et al., 2002). However, there is less evidence available about the relationship between HPV infection and cancer of the oral cavity.
The Human papillomavirus plays an etiological role in oropharyngeal cancer, with 25-50% of them related to HPV (DE MARTEL et al., 2017;CHATURVEDI et al., 2013). The higher prevalence of oropharyngeal HPV in men has been attributed to the greater propensity to smoke, considering the fact smoking interferes with mucosal immunity, increasing the susceptibility to HPV infection. Women are more likely to generate antibodies after a genital HPV infection than men, providing them some extra protection against oral HPV infection (GIULIANO et al., 2015).
In addition, women have a higher HPV genital viral count, making transmission more likely through male-to-female oral sex than female-to-male (GIULIANO et al., 2015). HIV-infected men are at higher risk of oropharyngeal HPV infection and cancer than HIV-negative men (DELANY-MORETLWE et al., 2013). Data on the prevalence of oropharyngeal HPV infection in low and middle-income countries is limited.
In the oral cavity, HPVs classified as low in oncogenic grade, such as subtypes 6 and 11, are the most frequently detected in benign oral lesions, such as common wart, acuminate condyloma, papilloma and focal epithelial hyperplasia. High-grade oncogenic subtypes, such as 16 and 18, on the contrary, have been strongly associated with squamous cell carcinomas and cancerous lesions, with a high risk of malignant transformation (D ŚOUZA et al., 2007).
HPV infection can be classified into: (a) latent, which can only be diagnosed by molecular biology methods; (b) subclinical, in which there are no clinical symptoms, but there are subtle changes that can be diagnosed, by peniscopy, colpocytology, colposcopy and / or biopsy; (c) clinical, in which there are evident lesions on clinical examination (TRISTÃO et al., 2012;XAVIER et al., 2007).

ONCOGENESIS AND THE ROLE OF VIRAL PROTEINS
There are about 200 different strains of HPV, of which nine are known to cause cancer, and another six are suspected of causing cancer. Among the various strains, HPV-16 is the main concern due to its association with OSCC. HPV-16 is also associated with cervical, anal and penile cancer (HPV ORAL CANCER FOUNDATION, 2019).
Numerous risk factors have been proposed in the oncogenesis of the OSCC, the most significant of them being the use of tobacco. There have been several explanations for the etiology of OSCC Disciplinarum Scientia. Série: Ciências da Saúde, Santa Maria, v. 21, n. 3, p. 45-64, 2020. 54 in a non-smoking population, including the human papilloma virus (HPV) and underlying genetic and transcriptomic changes. In particular, the development of this cancer in a younger, non-smoking population has been of interest to researchers (ZAMMIT et al., 2018).
Patients with HPV-positive OSCC exhibit a reduction in the risk of death by approximately half, compared to patients with HPV-negative tumors. Despite these better results, 10 to 30% of patients will experience disease progression within three years after the end of their definitive therapy.
HPV detection remains a predictor of improvement in overall survival rate for patients who experience progression of loco-regional and / or distant disease after initial treatment (BURR et al., 2018).
In a persistent infection scenario, the viral protein E2 controls the expression of the viral oncoproteins E6 and E7, which are primarily responsible for the formation of the tumor (MOODY; LAIMINS, 2010). In premalignant and malignant lesions, the E2 function is absent, which subsequently leads to uncontrollably higher levels of E6 and E7 expression (RAMPIAS et al., 2009). The inhibition of tumor suppressor proteins p53 and Retinoblastoma (pRb) alters the cell cycle pathways that regulate cell proliferation, apoptosis, as well as genetic stability, which can ulteriorly lead to the formation of epithelial lesions (AKGEUL, COOKE, STOREY, 2006). The binding of high-risk HPV E7 protein with pRb, results in the release of the transcription factor E2F from pRb-E2F and the consequent formation of the protein complex, promoting the progression of the cell cycle. In addition, it leads to the release of the p16INK4A gene from its transcriptional inhibition. As a consequence, the p16INK4A protein is expressed at high levels and is therefore considered as a reliable substitute marker for high-risk HPV infection (VON KNEBEL DOEBERITZ, 2001). Oral squamous papilloma is the most frequent lesion and occurs evenly among men and women, predominantly on the tongue and palate (FERRARO et al., 2011). The common wart has a higher incidence on the lips, and can also be located on the tongue, soft palate and hard palate (CARVALHO, 2016), they are usually isolated lesions, but not necessarily. It is suggested that these lesions can arise by self-inoculation, usually in people who have warts on their hands and fingers (ANTIENZO et al., 2015). Focal epithelial hyperplasia, also known as Heck's disease, is one that differs from the verrucous pattern of these lesions (FERRARO et al., 2011), presenting through papules or nodules, often involving the labial mucosa, occurs predominantly in children (ANTIENZO et al., 2015), this lesion is associated with HPV-13 and HPV-32 (CARVALHO, 2016;RATAUVA et al., 2011).

IDENTIFICATION METHODS
On other anatomical topographies, such as the genital tract, HPV exclusively infects the basal cells of the epithelium, where it can remain latent. There is evidence that HPV also infects gingival tissue (MADINIER et al., 1992;HORMIA et al., 2005). The periodontal pocket is the only location of the gingival mucosa where basal cells are exposed to the environment. The periodontal pocket increases during the progression of periodontitis as a result of chronic inflammatory processes (TEZAL, 2012). In the presence of chronic inflammation, increased basal cell proliferation leads to a higher viral load in the saliva, as well as an increased risk of HPV transmission. In a hospital-based casecontrol study with histologically confirmed OSCC cases, periodontitis was associated with a more than four-fold risk. This led to the hypothesis that chronic inflammation and continuous epithelial proliferation in the junction gum, could favor HPV replication and could be an important reservoir for HPV in the oral mucosa (STUBENRAUCH, LAIMINS, 1999). Disciplinarum Scientia. Série: Ciências da Saúde, Santa Maria, v. 21, n. 3, p. 45-64, 2020.
Since 2018, the quadrivalent HPV vaccine has been available for the female population aged 9 to 14 years old (14 years, 11 months and 29 days) and for the male population aged 11 to 14 years old (14 years, 11 months and 29 days) with a vaccination schedule of 2 (two) doses (0 and 6 months), via "Sistema Único de Saúde" (SUS -Brazil's public universal health system) (MINISTÉRIO DA SAÚDE, 2019).
HPV vaccination is expected to have an impact on oral HPV incidence rates, leastways for genotypes 6, 11, 16 and 18, included in the Gardasil 4 vaccine (BROUWER et al., 2015). Countries with more aggressive vaccination campaigns, such as Australia, already observe a reduction in HPV-related genital warts (ALI et al., 2013;CHOW et al., 2015). However, it has not been clarified yet whether HPV vaccination will in fact reduce the incidence and mortality of HPV-related cancers, as well as whether coverage and adherence to the vaccine will be adequate.

CONCLUSION
The current criteria for the classification of Papillomaviruses took over 15 years to be assembled, and even today new subtypes are frequently described in research. Many researchers made an attempt at explaining the role of the immune system in the clinical evolution of oral HPV, but many questions still remain unanswered. HPV has been found in malignant lesions of the oral cavity in a non-smoking patient, generating interest in research on oral cancer in non-smokers. Thence, it is believed that research improvement in the development of vaccines is absolutely crucial to understanding the best and safest way to control the disease.